This invention relates to Candida albicans surface adhesin proteins, to antibodies resulting from an immune response to vaccination with C. albicans surface adhesion proteins and to methods for the prevention and/or treatment of candidiasis and other bacterial infections with C. albicans surface adhesion proteins.
There has been a dramatic increase in the incidence of nosocomial infections caused by Candida species in recent years. The incidence of hematogenously disseminated candidal infections increased 11-fold from 1980 to 1989. This increasing incidence has continued into the 1990s. Infections by Candida species are now the fourth most common cause of nosocomial septicemia, are equal to that of Escherichia coli, and surpass the incidence caused by Klebsiella species. Furthermore Candida species are the most common cause of deep-seated fungal infections in patients who have extensive burns. Up to 11% of individuals undergoing bone marrow transplantation and 13% of those having an orthotopic liver transplant will develop an invasive candidal infection.
Candida albicans, the major pathogen in this genus, can switch between two morphologies: the blastospore (budding yeast) and filamentous (hyphae and pseudohyphae) phases. Candida mutants that are defective in genes regulating filamentation are reported to have reduced virulence in animal models. This reduced virulence suggests that the ability to change from a blastospore to a filament is a key virulence factor of C. albicans. To date, no essential effectors of these filamentation pathways have been identified in C. albicans. See Caesar-TonThat, T. C. and J. E. Cutler, “A monoclonal antibody to Candida albicans enhances mouse neutrophil candidacidal activity,” Infect. Immun. 65:5354-5357, 1997.
Staphylococcus aureus infections also are common and increasingly result in drug resistance to antibiotics. For example, S. aureus is a common cause of skin and skin structure infections, endocarditis and bacteremia in the U.S. and throughout the world. Formerly community acquired S. aureus (CA-S. aureus) infections were nearly uniformly susceptible to penicillinase-resistant beta lactams such as cefazolin, oxacillin, methicillin, penicillin and amoxicillin. However, over the past decade, epidemics of beta-lactam resistant S. aureus (MRSA) infection have been seen in multiple locales throughout the world, especially community acquired MRSA (CA-MRSA). In many places MRSA has become the predominant S. aureus strain causing CA infections. A recent, prospective, population-based survey in three states in the U.S. estimated that the incidence of CA-MRSA infections is 500 cases per 100,000 population, which translates to approximately 1.5 million cases per year in the U.S. alone. The increasing frequency of drug-resistant S. aureus infections highlights the need for new ways to prevent and treat these infections.
The identification of effectors in the regulatory pathways of the organism that contribute to virulence offers the opportunity for therapeutic intervention with methods or compositions that are superior to existing antifungal agents. The identification of cell surface proteins that affect a regulatory pathway involved in virulence is particularly promising because characterization of the protein enable immunotherapeutic techniques that are superior to existing antifungal agents when fighting a candidal infection.
The virulence of Candida albicans is regulated by several putative virulence factors of which adherence to host constituents and the ability to transform from yeast-to-hyphae are among the most critical in determining pathogenicity. While potent antifungal agents exist that are microbicidal for Candida, the attributable mortality of candidemia is approximately 38%, even with treatment with potent anti-fungal agents such as amphotericin B. Also, existing agents such as amphotericin B tend to exhibit undesirable toxicity. Although additional antifungals may be developed that are less toxic than amphotericin B, it is unlikely that agents will be developed that are more potent. Therefore, either passive or active immunotherapy to treat or prevent disseminated candidiasis is a promising alternative to standard antifungal therapy.
Thus, there exists a need for effective immunogens that will provide host immune protection and passive immunoprotection against Candida, S. aureus and other immunogenically related pathogens. The present invention satisfies this need and provides related advantages as well.